L34B - Drug Distribution 1 Flashcards
What is drug distribution?
The reversible transfer of drug from on site to another within the body
What are facts about blood circulation enables efficient drug distribution? (4) (numbers not asked)
- avg subject has 5L of blood = 3L plasma
- avg cardiac output is 5.5L/min at rest
- mixing of drug solution in the blood occurs very fast
- tissue distribution takes time, rate and extent depending on drug and tissues
What is cardiac output?
Amount of blood the heart pumps through the circulatory system in a minute
What is tissue differences in drug distribution and blood circulation?
Some tissues haev more drug flow, so potentially more exposure to drugs
What are the distribution (potential) steps? (2)
- passage of capillary membrane
- passage of cell membrane
What is paracellular movement of drug influenced by?
Tightness of the intercellular junctions
What are the 2 categories of transcellular pathways?
- those involving simple diffusion
- those involving facilitative mechs // transporters
What does movement of drugs across membrane occur through?
Paracellular and transcellular pathways
What are the distribution processes? (3)
- passive diffusion
- transporters
- hydrostatic pressure
What is hydrostatic pressure like? (2)
- arterial end pressure > tissue pressue
- tissue pressure > venous pressure
What is the movement like from capillaires to intersitial fluid (ISF)? (3)
- drug transport is independent of lipophilicity, charge and mol size
- easy paracellular trans
- larger molecules, charge is more important (-ve = lower perm across renal glomerulus)
What is the movement like from interstitial fluid (ISF) to cells? (2)
very dependent on:
- drug physicochemical properties (size, charge, lipophilicity)
- drug being substrate for influx/efflux transporters
What is drug transport across blood-brain barrier, hepatocyte and renal tubule highly dependent on? (3)
- lipophilicity
- charge
- molecular size
What are the effects of charge like? (2)
- large
- exceptions = paracellular transport across the blood capillary membranes and renal glomerulus)
What is membrane transport like for charged drugs? (2)
- slower
- degree of ionisation at physiological pH determines it
What is the pH partition hypothesis like? (4)
- assumes only un-ionised drug penetrates membranes
- at eq, conc of unionised species = on both sides
- at eq, conc of ionised species is > at the side with lower pH for a WB
- at eq, total conc is > at side with lower pH
What is the pH in the body? (5)
- gastric 1.5-7.0
- intestinal 6.2-7.5
- urine 5.0-7.5
- Elsewhere ~ pH of blood (7.4)
- excp. Acidic intracellular lysosomal region (pH 5)
What are transporters like from blood to tissues, into cells and back? (3)
- eq transporters vs active transporters/conc transporters
- efflux vs influx/uptake
- acpical side vs basolateral
What do transporters play an important role in? (3)
- distribution of some drugs
- absorption and elimantion of some drugs
- therapy success - resistance of tumour cells to some drugs, acess to target site
What are transporters as part of the brain blood barrier like from blood to tissues, into cells and back? (3)
- passage is highly dependent on lipophilicity, charge and molecular size
- permeability inc progessively with inc lipophilicity (not always)
- vinblastine and vincristine have permeability lower than expected, due to efflux PGP
What can drugs bind to? (3)
- tissue components
- plasma proteins
- RBCs
What is the binding eq in plasma like? (3)
- very fast
- usually reversible
- dif drugs bind to dif plasma proteins (acidic drugs to albumin, basic drugs to a1-acid glycoprotein, neutral compounds to lipoproteins)
What can bound drugs not do?
Diffuse across biological membranes - cannot cross capillary membranes
What is plasma binding a key determinant of?
Drug distribution
